Project Abstract Mild persistent activation of inflammatory pathways, often termed chronic inflammation (CI) is observed in up to 30% of older adults. Dozens of population studies have identified significant associations between serum- based pro-inflammatory measures and functional decline, frailty, worsening chronic illness, cognitive decline, mortality and reduced gait speed. Serum markers of CI such as interleukin 6 (IL6) and soluble TNF-alpha receptor 1 (sTNFR1) are increasingly recognized as pathologic and in part causal in many of age-associated processes such as sarcopenia and neurodegeneration that in turn drive functional and cognitive decline and worsening chronic disease states in older adults. Despite the increased understanding of etiologies and consequences of CI in older adults, few options have been tested for reducing CI and associated adverse health outcomes. Our research team has been actively engaged in the study of CI and its etiologies and consequences and have worked to develop inflammatory phenotypes that help to identify those older adults with CI. Building on that research experience and infrastructure, and on clinical Geriatrics expertise, that same team has worked to identify biologically relevant interventions. Lactoferrin is a basic glycoprotein found in most exocrine secretions and in neutrophil granules that has a pleiotropic impact on innate immune system activation and attenuates inflammation. Importantly, a recombinant human lactoferrin (rhlactoferrin) in capsule form has recently been developed, which has enabled accurate dosing and the development of a placebo control capsule necessary for a pilot clinical trial in human subjects. We hypothesize that oral rhlactoferrin will attenuate inflammatory signaling in adults with CI. We further hypothesize that the lactoferrin induced CI attenuation will attenuate decline or facilitate measureable improvement in specific functional and cognitive measures in older adults. The specific aims of this proposal are 1) To determine the ability of oral rhlactoferrin to reduce CI as measured by serum IL6 and sTNFR1 in older adults in a 6 month placebo-controlled pilot study, 2) To determine the tolerability and adherence of rhlactoferrin among those older adults with chronic inflammation over a 6 month treatment period, and 3) To gather pilot data on the influence of rhlactoferrin treatment over 6 months on measures of cognitive and physical function known to be influenced by CI. At the conclusion of this pilot study, we will have determined whether rhlactoferrin can significantly reduce measures of CI, if it is safe and tolerable for older adults, and if it has the potential to meaningfully influence important markers of physical and cognitive function known to be influenced by CI. This information will in turn be utilized to develop a more definitive clinical trial of rhlactoferrin for CI and adverse health outcomes in older adults.